DESCRIPTION: a. Candidate: Dr. Yang-Xin Fu received his M.D. degree in 1983 from the Shanghai Medical University in China and his Ph.D. degree in immunology from the University of Miami in 1990. From 1991-93 he was a Research Associate in the Division of Infectious Diseases at the National Jewish Center for Immunology and Respiratory Medicine in Denver. Since 1994 he has been a Resident in the Division of Laboratory Medicine, Department of Pathology, Washington University School of Medicine in St. Louis. b. Sponsor: David Chaplin, M.D., Ph.D., is Professor of Medicine, Genetics and Molecular Microbiology at Washington University in St. Louis. He has been Associate Investigator at the Howard Hughes Medical Institute in St. Louis since 1984 and is currently the Chief, Division of Allergy and Immunology, the Washington University School of Medicine. c. Career Development Plan: The candidate desires to gain experience in developing, analyzing and maintaining transgenic and knock-out mice. The career development plan also includes training in immunochemistry, flow cytometry, preparation of bone marrow chimeras, and in analysis of the maturation of the B-lymphocyte response. For the last one to three years of the award Dr. Fu will be appointed as an Instructor in Pathology so that he may direct an increasingly independent program. No formal course work is proposed. However, the candidate will take an English writing skills course so that his writing abilities can match his oral communication skills. He will devote 90 percent effort to the research project. d. Research Plan: The overall goal of the project is to define the role of peripheral lymphoid structures in the maturation of the host immune response and to identify essential actions of lymphotoxin (LT) in the regulation of these responses. The candidate states that the functions of lymphotoxin alpha (LT-alpha) need to be reevaluated in light of the discovery of a receptor for the heteromer of LT-alpha and lymphotoxin beta (LT-beta), called TNFRrp, and in light of the observation that LT-alpha deficient mice (LT-alpha-/-) do not develop lymph nodes or Peyer's patches. The project is based on the hypothesis that LT plays an important role in the induction of contact sensitivity responses and that it may play a role either directly or indirectly in regulating Ig class switching after immunization with different antigens. Dr. Fu's preliminary research shows that LT-alpha deficient mice exhibit an impaired contact sensitivity response but mount a good cutaneous hypersensitivity response. In addition, these mice demonstrate impaired Ig class switching following sheep red blood cells (SRBC) challenge but normal Ig class switching following OVA immunization. These results suggest that the type of antigen and the structure of the antigen might determine the necessity for LT-alpha lymph nodes or Peyer's patches in generating normal immunoglobin responses. Dr. Fu's group has also demonstrated an impairment in IgA production in the LT-alpha-/- mouse. Bone marrow cell transfer from normal mice does not restore the development of Peyer's patches but does increase IgA production, suggesting there may be a dichotomy between the need for Peyer's patches and IgA production. The aims of the project are to: 1) investigate the role of LT-alpha in contact sensitivity, 2) test the role of LT-alpha and its receptors in Ig class switching, and 3) define the role of Peyer's patches and lymphotoxin in the immune response to orally administered antigens using normal and LT-alpha knock-out mice. e. Environment: The candidate will carry out his research at the Howard Hughes Medical Institute, Washington University School of Medicine, in the laboratories of the Clinical Sciences Research Building.